Our goal is to define the mechanisms responsible for maternal circulatory adaptations to normal pregnancy. Using the gravid rat model which manifests circulatory changes comparable to pregnant women, we showed that endothelin via the ETB receptor subtype on endothelium mediates nitric oxide (NO)-dependent renal vasodilation and hyperfiltration in vivo, as well as reduced myogenic reactivity of small renal arteries in vitro. We further showed that the pregnancy hormone, relaxin (RLX), vasodilates the renal circulation via ET/NO when administered to nonpregnant rats, and by neutralizing endogenous circulating RLX with antibodies, the renal circulatory adaptations of pregnancy are abrogated. Based on these findings, four hypotheses are proposed which test the role of RLX in additional cardiovascular adaptations to pregnancy. Hypotheseis 1. Cardiac output and global arterial compliance (AC) in conscious rats, as well as the compliance of large and small arteries in vitro, rise concurrently during pregnancy. Hypothesis 2. Cardiac output and global AC in conscious, intact or ovariectomized rats, as well as the compliance of large and small arteries in vitro, rise concurrently during chronic administration of recombinant human relaxin (rhRLX), thereby mimicking the pregnant condition. Hypothesis 3. The rise in cardiac output and global AC of pregnancy in conscious rats, as well as the increase incompliance of large and small arteries in vitro, are abrogated by chronic administration of RLX neutralizing antibodies or by ovariectomy. Hypothesis 4. Pregnancy-related increases in large and small artery compliance are compromised in mice without a functioning relaxin gene. In summary, we suggest that RLX mediates both the decline in systemic vascular resistance and the rise in global AC during pregnancy, thereby initiating increases in cardiac output while maintaining diastolic pressure and preserving efficient coupling of the ventricular and arterial systems. We further propose that vascular remodeling as well as reduced arterial tone mediate the rise the rise in global AC. Both the well-know matrix-degrading properties and newly discovered renal vasodilatory attributes of RLX make this hormone a leading candidate responsible for these major cardiovascular changes in pregnancy. Our preliminary data are exciting because thy support the hypotheses. Knowledge of the pregnancy hormone(s) underlying these remarkable circulatory changes is crucial for complete understanding of maternal adaptation to normal pregnancy, will likely facilitate investigation of preeclampsia in which the vasodilatory response is inappropriate, and may provide new treatment(s) to combat vascular aging and hypertension in the nonpregnant population.